Purpose and Methods: The goals of this ongoing study are 1) to evaluate the role of dopamine (DA) in the subjective and behavioral effects of d-amphetamine in normal volunteers and 2) to explore the effects of the combined administration of a DA agonist and antagonist in blocking amphetamine reward. Studies with laboratory animals have demonstrated a role for DA in mediating the rewarding effects of amphetamine but studies with humans have provided inconsistent results. We are exploring the role of DA by comparing the subjective and behavioral effects of amphetamine after pretreatment with placebo, a DA agonist and a DA antagonist. We also aim to determine the extent to which combined pretreatment with a DA agonist and antagonist produces greated reduction of amphetamine's effects than either treatment alone, in an effort to extend previous findings in cigarette smokers. The study is conducted according to a 2 (Agonist: d-amphetamine [AMP] or placebo [PLAC]) x 2 (Antagonist: haloperidol [HAL] or PLAC) x 2 (Challenge drug: AMP or PLAC) mixed within- and between subjects design. The pretreatment drugs are within- subjects manipulations, whereas the challenge drug condition varies between subjects. All drugs are administered under double-blind conditions, with the order of conditions counterbalanced across subjects. We hypothesize that both haloperidol and d-amphetamine will attenuate subjective (e.g., euphorigenic) responses to the challenge dose of d-amphetamine, but that combined pretreatment with haloperidol and d-amphetamine will attenuate responses to the challenge dose to a significantly greater extent. Furthermore, we expect the combined pretreatment condition to produce a better side effects protocol than either pretreatment drug alone. Results: Preliminary data from 25 subjects supports our hypotheses. For example, pretreatment with both amphetamine and haloperidol attenuated euphorigenic responses to d- amphetamine; combined pretreatment attenuated responses to a greater extent than either pretreatment alone. Moreover, amphetamine and haloperidol offset the side effects of each other. For instance, haloperidol produced a slight decrement in psychomotor performance, which was reversed by the addition of amphetamine. These preliminary results suggest that this treatment approach should be studied further. Significance and future plans: Studies with laboratory animals have consistently demonstrated a role for dopamine (DA) in the effects of amphetamine related to its abuse, but to date no dopaminergic agents have proven effective in treating stimulant abuse. The lack of efficacy of dopaminergic agents may relate to differences in the role of DA in animals as compared to humans, or to limitations in the doses of the treatment drugs that can be tested. This study will directly address both issues. We will determine whether the effects of a dopaminergic agonist and antagonist on responses to amphetamine in humans suggest a significant role for DA in humans. In addition, we will explore the effects of an agonist/antagonist combination on responses to amphetamine. To date, DA agonists and antagonists have not been well tolerated at the doses required for treatment of stimulant addiction; DA agonists can produce unpleasant side effects and may have abuse potential of their own, and DA antagonists are aversive and can produce long lasting and permanent motor side effects after prolonged use. Based on previous work with nicotinic agonist/antagonist combinations and smoking cessation, the combined drug treatment would be expected to have less abuse liability and to produce fewer side effects than either drug alone, and should block the positive rewarding effects (e.g., euphoria) of d-amphetamine. The potential usefulness of this treatment approach for stimulant drug abuse cannot be underestimated since no effective treatments are available at this time. If the results of this study are promising, future studies will explore the effects of these and other dopaminergic treatments and combinations in both normal volunteers and in patients with diagnoses of stimulant abuse and/or dependence.